Abstract 695: Ocrelizumab, a Novel Humanized Anti-CD20 Antibody: Week 72 Results from a Phase I/II Clinical Trial in Patients with Rheumatoid Arthritis
Authors
M Genovese, J Kaine, M Lowenstein, J DelGiudice, A Baldassare, J Schechtman, E Fudman, M Kohen, S Gujrathi, R. Trapp, N Sweiss, G Spaniolo, W Dummer.
Background:
Ocrelizumab is a humanized monoclonal antibody directed against CD20 expressed on B Cells. The 24 week results of this large Phase I/IIa safety in DMARD refractory patients (ACTION) was previously reported and summarized at ACR 2006. http://www.hopkins-arthritis.org/physician-corner/education/acr2006/RA/B-Cell-Depletion/RA-B-Cell-Depletion-Abstract-6.html. The presentation at ACR focused on longer term safety and efficacy.
Purpose:
The primary objective was to evaluate the safety and tolerability of ocrelizumab (OCRA) plus methotrexate (MTX) in moderate-severe, rheumatoid factor positive RA patients. Secondary objectives included dose-response analysis of B-cell pharmacodynamics and clinical activity.
Methods:
Safety over the entire 72-week study period and efficacy through Week 24 are reported. ACTION was a combined Phase I/II study of 237 pts with an inadequate response to at least MTX. Pts remained on stable doses of MTX (10-25 mg/wk) and were randomized to a single course of ocrelizumab (10, 50, 200, 500, 1000 mg) or placebo by IV infusion on Days 1 and 15. No IV corticosteroids were given before infusions. Clinical assessments were made every 4 weeks between baseline and Week 24, and then every 12 weeks through Week 72 study.
Results:
237 (196 ocrelizumab, 41 placebo) pts comprised the intent-to-treat (ITT) population. Demographic characteristics were similar, including prior use of TNF inhibitors (47%). Most frequent adverse events (AEs) were infusion-associated Grade 1-2 headaches, nausea, chills, pyrexia, and dizziness. Infusion-associated AEs following the first infusion were similar among ocrelizumab doses and more frequent than in placebo, but similar to placebo after the second infusion. Rates of SAEs and infection-related AEs and SAEs were similar among groups. B-cell depletion was observed with all doses of ocrelizumab, with earlier B-cell reconstitution at lower doses. There was a median decrease in IgM by 15-20% from baseline levels but largely maintained above the lower limit of normal. There was no association observed between the reductions and infections.
Clinical responses at 24 weeks have previously been reported with the best ACR 20/50/70 responses (50%/27.5%/17.5% versus 22%/7.3%/2.4%, OCRA vs placebo respectively) observed with the highest dose of Ocrelizumab (1000 mg x 2). Human anti-human drug antibodies (HAHAs) were low at higher doses (19%, 10%, 0, 0, 5.0% for 10, 50, 200, 500, 1000 mg x2).
Conclusions:
Ocrelizumab with MTX was well tolerated over 72 weeks with clinical activity at all doses at 24 weeks. Doses of ≥200 mg x 2 showed the best efficacy and reduction in CRP, and lowest immunogenicity (HAHA).
Editorial Comment:
This was a large Phase I/IIa study of a humanized antibody directed against CD20 in DMARD refractory RF-positive RA patients, 47% of whom also failed TNF antagonists. The study is notable for the fact that no IV steroids were given. With relatively low placebo responses, the ACR 20/50/70 responses were encouraging at 24 weeks and confirm that agents targeting anti-CD20 is a reasonable target or at least a group of patients with RA. B cell depletion was long-lived with this antibody. The time course of clinical response was not reported, though CRP reductions were seen at 12 weeks, nor were data presented regarding loss of response. The study design however allowed patients to receive rescue treatment after 24 weeks with other agents, thus making any interpretation of loss of response information difficult. Even though this is a humanized antibody, first dose infusion-related reactions were more frequent than in the placebo group, thus raising questions as to whether the mechanism explaining these reactions are mechanism based anti-CD-20 mediated cell effects rather than a phenomenon related to chimeric versus humanized versus human antibody construct. The reductions reported in IgM levels is similar to that reported for Rituximab. Whether repeat administration of this drug will be associated with continuing reductions in immunoglobulin levels has not been reported.
